Ichthyosis follicularis, atrichia and photophobia (IFAP) and hereditary mucoepithelial dysplasia: Two syndromes that share a common clinical spectrum

Abstract

Ichthyosis follicularis, atrichia and photophobia syndrome (IFAP) is an X‐linked inherited disease caused by pathogenic variants in the gene encoding the membrane‐bound transcription factor peptidase, site 2 (MBTPS2). Clinical presentation includes ichthyosis follicularis, alopecia, photophobia and developmental delay. Hereditary mucoepithelial dysplasia (HMD) is a dominantly inherited disease characterized by keratitis, non‐scarring alopecia, skin lesions including follicular keratosis, perineal erythema, and mucosal involvement. Recently, variants in SREBF1, a gene coding for a transcription factor related to cholesterol and fatty acid synthesis, have been associated with the disease. These two syndromes share a common clinical spectrum. Here, we describe an IFAP syndrome patient with a novel variant in the MBTPS2 gene and an HMD patient with a previously reported variant in the SREBF1 gene. In addition, we present a review of the literature describing the triad characterized by non‐scarring alopecia, keratosis follicularis, and ocular symptoms common in both IFAP and HMD patients to raise awareness of these underdiagnosed diseases. We also highlight the subtle differences in clinical presentation between the two disorders to better enable differentiation.

An intronic splice‐site variant in MBTPS2 underlies ichthyosis follicularis with atrichia and photophobia syndrome

“…In addition, one start codon variant and three intronic variants in MBTPS2 were reported to cause IFAP triad along with many variable features. 2,[10][11][12] Interestingly, one male carrying an intronic variant c.671-9T>G showed extra features of palmoplantar and periorificialkeratoderma, reminiscent of Olmsted syndrome. 10 Olmsted syndrome is characterized by the presentation of bilateral mutilating palmoplantar keratoderma and periorificial hyperkeratotic plaques.…”

“…Although the variant was previously reported in an Argentinian boy who had clinical features of IFAP triad, global developmental delay, and absence seizures, the nature of the variant was not elucidated by the study. 2 We identified the pathogenicity of the variant via direct cDNA sequencing and a mini-gene assay. When evaluating the effect of splice-site variants, direct cDNA sequencing can be chosen as the first option if fresh samples are available and mini-gene assays as an alternative if samples are not available in time.…”

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Ichthyosis follicularis with atrichia and photophobia (IFAP) syndrome is a rare human oculocutaneous disorder with no more than 100 cases reported in literature since it was first described by Mcleod in 1909. 1,2 Prominent characterizations of the disorder are thornlike follicular hyperkeratosis, nonscarring alopecia, and photophobia with variable severity. 3 Additional manifestations may include dry skin, psoriasiform plaques, eczema, angular cheilitis, nail dystrophy, hypohidrosis, recurring infections, genitalia anomalies, inguinal hernia, developmental delay, brain anomalies, seizures, intellectual disability, hearing deficit, skeletal abnormalities, short stature, cleft hand, finger abnormalities, mucosal involvements, as well as many other anomalies.

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“…3 Additional manifestations may include dry skin, psoriasiform plaques, eczema, angular cheilitis, nail dystrophy, hypohidrosis, recurring infections, genitalia anomalies, inguinal hernia, developmental delay, brain anomalies, seizures, intellectual disability, hearing deficit, skeletal abnormalities, short stature, cleft hand, finger abnormalities, mucosal involvements, as well as many other anomalies. 2,4,5 As the vast majority of cases featuring IFAP triad are male, an Xlinked mode of inheritance was predicted. The existence of several female patients with IFAP triad indicated an alternative autosomal dominant inheritance.…”

Ichthyosis follicularis syndromes in patients with mutations in GJB2

“…Ichthyosis follicularis (IF) is a distinct syndromic form of ichthyosis, which has been reported in association with atrichia and photophobia (IF-alopecia-photophobia syndrome), caused by mutations in the genes SREBF1 and MBTPS2. 1 IF with bilateral sensorineural hearing loss (SNHL) and palmoplantar keratoderma (PPK) was previously shown in two families with autosomal recessive mutations in the Gap junction beta 2 gene (GJB2), encoding Connexin 26 (Cx26). 2 Germline GJB2 mutations have been associated with keratitis-ichthyosis-deafness (KID) syndrome.…”